OBJECTIVE: The objectives of this project are (1) to examine hypotheses relating to the etiology and prevention of upper gastrointestinal (UGI) cancers, and (2) to develop successful clinical strategies for the early detection and treatment of these cancers. BACKGROUND: Gastric and esophageal cancers are the second and sixth most common causes of cancer death worldwide. Both of these cancers have a very poor prognosis, largely because symptoms usually do not occur until late in the disease. Significant reduction in UGI cancer mortality will probably require development of new prevention strategies based on identification of modifiable risk factors and development of new methods to diagnose and treat more cases at earlier, more curable stages of disease. Both etiologic and early detection studies are most efficiently done in high-risk populations, so many of the studies in this project are performed in such populations. METHODS: (1) Etiologic studies: (a) China: Between 1985 and 1991, we conducted two randomized nutrition intervention trials (NIT), in Linxian, China, a county where cumulative death rates due to esophageal squamous cell carcinoma and gastric cardia adenocarcinoma exceed 20%. These trials, with a combined enrollment of nearly 33,000, evaluated the effect of supplementation with several vitamin/mineral combinations on UGI cancers and found significant reductions in total mortality and gastric cancer mortality among those taking a combination of selenium, beta-carotene and vitamin E. Since 1991, we have followed the NIT participants as a cohort, and have performed nested studies evaluating the association between baseline characteristics and later development of UGI cancers. (b) Iran: We are currently conducting a case-control study (300 cases, 600 controls) of esophageal squamous cell carcinoma (ESCC) in Golestan Province, Iran, another population with very high rates of ESCC. Comparing results from high-risk populations in Iran and China, which are quite distinct geographically, ethnically and culturally, should give us insight into which environmental and genetic risk factors are most important for the development of this disease. (c) Other: We have begun preliminary studies evaluating PAH exposure in high ESCC risk populations in southern Brazil and in western Kenya. (2) Early Detection and Treatment studies: This part of the project includes four studies: (a) the Cytology Sampling Study (CSS), to develop practical and accurate primary screening tests for esophageal squamous dysplasia and early ESCC; (b) the Mucosal Staining Study (MSS), to develop methods for endoscopic localization of squamous and glandular dysplasia of the esophagus and stomach; (c) the Endoscopic Therapy Pilot Study (ETPS), to evaluate new techniques for endoscopic treatment of high-grade squamous dysplasia and early ESCC; and (d) the Chemoregression Study (CRS), to test chemoprevention strategies to reduce progression and increase regression of low-grade esophageal squamous dysplasia. PROGRESS: (1) Etiologic studies: (a) China: Recent results from nested studies in the NIT cohort have shown: (i) a strong association between low serum selenium levels and increased ESCC and gastric cardia cancer risk; (ii) no relation between serum carotenoids and risk of UGI cancers; (iii) a strong association between low serum alpha-tocopherol levels and increased ESCC risk; (iv) a strong association between low tissue zinc levels and increased ESCC risk; (v) increased risk for both cardia and non-cardia gastric cancer among subjects with positive serology for H pylori; (vi) no association between positive serology for HPV 16, HPV 18, or HPV 73 and ESCC, gastric cardia cancer or non-cardia gastric cancer; (vii) no relation between fumonisin exposure and ESCC risk; (viii) an association between tooth loss and risk of UGI cancers; (ix) an association between self-reported goiter and non-cardia gastric cancer.